PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis

Jiadong Wang, Justin Wai Chung Leung, Zihua Gong, Lin Feng, Xiaobing Shi, Junjie Chen

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Mutation of PHF6, which results in the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression.

Original languageEnglish (US)
Pages (from-to)3174-3183
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number5
DOIs
StatePublished - Feb 1 2013

Fingerprint

Cell Cycle
Ribosomal RNA
Cells
Ribosomal DNA
DNA Damage
Tumors
DNA
X-Linked Mental Retardation
T-cells
Genomic Instability
G2 Phase
RNA Stability
Cell proliferation
Transcription
Cell Cycle Checkpoints
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genetic Promoter Regions
Acute Myeloid Leukemia
Cell Division
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis. / Wang, Jiadong; Leung, Justin Wai Chung; Gong, Zihua; Feng, Lin; Shi, Xiaobing; Chen, Junjie.

In: Journal of Biological Chemistry, Vol. 288, No. 5, 01.02.2013, p. 3174-3183.

Research output: Contribution to journalArticle

Wang, Jiadong ; Leung, Justin Wai Chung ; Gong, Zihua ; Feng, Lin ; Shi, Xiaobing ; Chen, Junjie. / PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 5. pp. 3174-3183.
@article{9161e5e74b6f41a6a4636236d3e4c3a2,
title = "PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis",
abstract = "Mutation of PHF6, which results in the X-linked mental retardation disorder B{\"o}rjeson-Forssman-Lehmann syndrome, is also present in about 38{\%} of adult T-cell acute lymphoblastic leukemias and 3{\%} of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression.",
author = "Jiadong Wang and Leung, {Justin Wai Chung} and Zihua Gong and Lin Feng and Xiaobing Shi and Junjie Chen",
year = "2013",
month = "2",
day = "1",
doi = "10.1074/jbc.M112.414839",
language = "English (US)",
volume = "288",
pages = "3174--3183",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "5",

}

TY - JOUR

T1 - PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis

AU - Wang, Jiadong

AU - Leung, Justin Wai Chung

AU - Gong, Zihua

AU - Feng, Lin

AU - Shi, Xiaobing

AU - Chen, Junjie

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Mutation of PHF6, which results in the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression.

AB - Mutation of PHF6, which results in the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression.

UR - http://www.scopus.com/inward/record.url?scp=84873303336&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873303336&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.414839

DO - 10.1074/jbc.M112.414839

M3 - Article

C2 - 23229552

AN - SCOPUS:84873303336

VL - 288

SP - 3174

EP - 3183

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 5

ER -